Vascular endothelial growth factor (VEGF) is a major pathogenic factor for wet age-related macular degeneration (AMD) and diabetic retinopathy (DR), leading causes of blindness in the US. Intensive studies on wet AMD and DR have led to the development of anti-VEGF strategy for treating blood-retina barrier (BRB) breakdown in these diseases. To investigate the functional significance of VEGF signaling in major retinal supporting cells, Mller glia, we disrupted VEGF receptor-2 (VEGFR2) in mice and observed a significant loss of Mller cells, accelerated retinal neuron degeneration, and a substantial reduction of two neurotrophins: brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) in the retina in diabetes/hypoxia. In this study, we will determine the mechanism of VEGF signaling-mediated Mller cell viability, evaluate the significance of VEGF signaling in the production of neurotrophins, and explore therapeutic potential of supplying neurotrophins for neuroprotection in diabetic or hypoxic animals. Our study will contribute to the basis for establishing a general strategy to treat neuronal pathology in DR and other hypoxic retinal diseases and provide mechanistic insights for Mller glia as a cellular source of neuro-protectants in these diseases.